Proper establishment of jaw length is essential to feeding, breathing, and normal development of oral-motor skills. Micrognathia, also referred to as mandibular hypoplasia, is a condition where the jaw is undersized. Treatment for craniofacial defects such as micrognathia often involves multiple surgical interventions, a lengthy, costly, and emotionally and physically draining process. Prevention, therefore, provides a welcome alternative for at-risk individuals. Identifying potential strategies for rescue or regeneration depends, however, on an understanding of the developmental processes regulating jaw size. The jaw, along with most of the craniofacial skeleton, derives from the neural crest (NC), which is a transient, multi-potent cell population that arises at the border of the neural plate. The size of jaws may be directly linked to the size of the progenitor population (i.e., number) of NC. At least three parameters are likely to contribute to variation in NC number: the number of cells that are specified as NC precursors (as opposed to neuroepithelial or ectodermal precursors), the rate of NC cell death, and the rate of NC proliferation. In fact, several studies have closely associated micrognathia with a change in NC number as a result of decreased NC proliferation or increased NC death. Our preliminary analyses indicate that species-specific differences in jaw size arise during development and may be associated with differences in NC number. We hypothesize that the number of neural crest cells regulates jaw size and that species-specific differences in jaw size arise from evolutionary changes in the number of NC precursors, the rate of NC survival and/or the rate of NC proliferation. To test our hypothesis, we will manipulate the number of NC precursors, modulate NC cell death, alter NC proliferation, and assess the effect of these treatments on jaw size. Our proposal has three Specific Aims, focusing on the lower jaw skeleton and investigating the role of three parameters likely to contribute to jaw size. Specific Aim 1 will determine if the number of cells specified as NC precursors regulates jaw size. Specific Aim 2 will determine if differences in survival of NC contribute to differences in jaw size. Finally, Specific Aim 3 will determine if proliferation rates of NC regulate jaw size. Results will be analyzed on molecular, cellular, histological and morphological levels. This project is significant because an understanding of developmental mechanisms regulating jaw size will contribute to the establishment of biologically based preventative therapies. PUBLIC HEALTH RELEVANCE: What controls jaw size? Answering this question is important for preventing birth defects, as well as for devising new therapies to repair or regenerate bones affected by injury or disease. The goal of this project is to identify cell biological mechanisms that determine jaw length.